Human Fc receptors (FcgammaR) are now recognized to consist of three families with multiple distinct genes, alternative splicing variants, and allelic forms leading to extensive diversity of structure and function. Recent advances bring into focus three observations pertinent to SLE: 1) FcgammaRIIA is a crucial receptor mediating phagocytic function; 2) activation of FcgammaRIIA is characterized by enhanced binding and phagocytic capacity which is unrelated to changes in quantitative expression; and 3) the LR allele of FcgammaRIIA is the only human FcgammaR which recognizes IgG2 efficiently. In SLE, Fcgamma receptor-specific clearance of IgG-sensitized autologous erythrocytes by the mononuclear phagocytes system is impaired. This defect is dynamic and closely related to both renal and nonrenal disease activity, emphasizing the importance of FcgammaR dysfunction in immune complex deposition and the pathogenesis of SLE. Despite this decrease in FcgammaR-mediated clearance, there is a paradoxical increase in monocyte FcgammaR binding capacity for EA in vitro, without a difference in cell surface expression of any class of FcgammaR. Preliminary data indicate that FcgammaRIIA is a compelling candidate responsible for the FcgammaR dysfunction in SLE. Specific studies of FcgammaRII on monocytes in SLE patients has revealed significantly increased FcgammaRIIA-mediated binding, but markedly decreased FcgammaRIIA- mediated phagocytosis, indicating dissociation of receptor-effector coupling. Based on these observations we hypothesize that 1) abnormal FcgammaRIIA function provides a basis for the disease-related defects and abnormal handling of IgG2 subclass containing immune complexes in SLE, and 2) that alleles of FcgammaRIIA and novel forms of FcgammaRIIA with distinct functional capacities may be of important clinical significance as heritable disease susceptibility factors. Therefore, the specific aims of this proposal are: 1. to understand the basis of activation of FcgammaRIIA, (a) to define the mechanism of the increase in binding by FcgammaRIIA in activated cells (b) to define the mechanism of the induced increase in phagocytic efficiency by FcgammaRIIA; 2. to define the counterbalancing effects leading to the defect in phagocytosis by FcgammaRIIA in SLE; 3. to define the role of FcgammaRIIA alleles in relation to pathogenic IgG2 autoantibodies and renal disease in SLE; 4. to study several unique SLE patients with profound abnormalities in FcgammaRIIA function to define potential novel receptor forms. We will focus on identification of FcgammaRIIA as the target receptor for pathogenesis of immune complex-mediated autoimmune diseases. With this information we will be able to define heritable and acquired components of FcgammaR dysfunction in SLE and modulate receptor function to therapeutic advantage.